In recent years, the use of various herbs and/or herbal medical products for the prevention of disease, alleviating the effects thereof, or for treating diseases have been gradually increasing in all societies. Throughout the human history, there have been and still are attempts for treating many diseases (diabetes, jaundice, dyspnea, etc.) by using some herbs. According to the records of the World Heath Organization (WHO), a large proportion of the world's population (70-80%) makes use of herbs for therapeutic or prophylactic purposes. Additionally, around 25% of prescription drugs in developed countries are composed of plant based active agents (vinblastine, reserpine, quinine, aspirin, etc.) (Farnsworth et al., 1985).
Particularly following the end of the 1990s, the discovery of new areas of use for medical and aromatic herbs and the increasing demand for natural products have increased the use potential thereof day by day.
Herbal medical products have long been widely used for the treatment or prophylaxis of respiratory diseases. In the treatment or prophylaxis of these diseases which are typically caused by viruses, bacteria, and/or fungi, it is quite significant both to eradicate these harmful organisms and to boost the immune system of the affected individual. This is because the immune system is comprised of processes providing protection against diseases, as well as recognizing and eliminating the pathogenic and tumor cells in a living being. The system scans the organism against any kind of foreign substances, entering or contacting the former, from viruses to parasitic worms of a wide variety, and distinguishes them from the organism's own healthy cells and tissues. The immune system can even distinguish substances with very similar features from each other to such an extent that even proteins having a different amino acid can be distinguished from the equivalents thereof. The function of the immune system is primarily to prevent harmful foreign substances from entering the respective organism, or upon entry, to retain the substances at the place of entry, or to prevent or delay their spreading therein.
Hedera helix (English Ivy) is one of the plant species used in the production of herbal products for the treatment and prevention of diseases, and/or for the alleviation and/or elimination of the symptoms thereof. Hedera helix, comprising saponins, phenol, and alkaloids, is known to be used for the treatment of cough, parasites, skin diseases, bronchitis, and chronic respiratory tract diseases. Various studies have been performed to demonstrate the effect of Hedera helix on said diseases. For instance, Erik van Wyk and Michael Wink stated in “Medicinal Plants of the World” that the expectorant action of Hedera Helix works by stimulating the “nervus vagus” in the stomach, causing a cough response. A study by S. Fazio et al. published in the January 2009 issue of “Phytomedicine” tested a dried leaf extract on 9657 patients with acute and chronic bronchitis, including children. Accordingly, it was observed that following one week, cough and chest pain disappeared or improved in 95% of patients.
Pelargonium sidoides (African Geranium, Umckaloabo) is a plant species widely used in the treatment and prevention of, or in the alleviation and/or elimination of the symptoms of cold and respiratory tract disease (pharyngitis, sinusitis, acute bronchitis, tonsillitis). It was determined to be effective in increasing the generation of natural killer cells and tumor necrosis factor alpha, and to enhance the release of interferon beta. Pelargonium sidoides has antiviral properties strengthening the immune system. It further has both antibacterial effects and antioxidative properties against some bacteria. Apart from that, it was also reported to boost the immune system of the respective organism and to have expectorant action by increasing the ciliary beat frequency of respiratory epithelial cells. In a multicenter study conducted by the Pneumology Department of a German University Hospital (2000) on acute bronchitis patients, including adults, children, and infants, it was determined that an extract of the roots of Pelargonium sidoides reduced the severity of the symptoms after 7 days treatment from 6.3 to 0.9 according to the average bronchitis severity score. A study published in “Acta Paediatrica” in April 2010, showed that preparations extracted from herbal roots were much more effective in the treatment of acute bronchitis as compared to placebo. A study group of children aged 6 to 18 years, taking the herbal extracts experienced less coughing, sputum, and bed rest times versus placebo. By assessing the results of four placebo-controlled clinic trials, the researchers at the Medical Center, the University of Pittsburgh, concluded that a standardized extract of Pelargonium sidoides showed a much better performance in alleviating the bronchitis symptoms versus placebo in a 7-day treatment period.
Ginger, Zingiber officinale, is also called “warming herb” and used for a long time as an important medical herb. It comprises essential oils with ether comprising Zingiberene, Zingiberol, Gingerol and Shogol. The essential oils contained which are mixed with terpenoids give the special taste and scent of ginger. The bitter substances without essential oils which make the mouth feel warm are gingerol and zingeron.
Ginger has a wide area of usage. Ginger is preventive against cancer based on stopping the Epstein-barr virus activity. 6-gingerol and 6-paradol, among the active substances of ginger, are effective in stopping promyelocytic leucaemia by disturbing the DNA synthesis. It also has anti-inflammatory effect, is effective against arthritis and headache, and is bacteriostatic. It is used against nausea, spasm and fever in kids. Based on its antiseptic effect, it is used against stomach and intestine infections and even against food poisoning. It also prevents the coagulation of the blood and has blood thinning effect. It supports the cardiovascular system by making the platelets less adherent, this in turn causes a decrease in the problems of circulation system. It is appetizing and can also be used against constipation. In addition to these, it has a warming and sedative effect in cough, flu, cold and other respiratory system diseases.
In prior art, there are many formulations, which comprises herbal agents or combinations of herbal agents, are disclosed. For example, WO2009/011498 A1 discloses a composition for the treatment of infection in the form of a syrup comprising Pelargonium sidoides; EP1829548 A1 discloses a composition comprising an extract of Pelargonium sidoides; KEMMERICH BERND at al.: “Efficiency and tolerability of a fluid extract combination of thyme herb and ivy leaves and matched placebo in adults suffering from acute bronchitis with productive cough. A prospective, double-blind, placebo-controlled clinical trials” (ARZNEIMITTEL FORSCHUNG. DRUG RESEARCH, Acv EDITO CANTOR VERLAG, AULENDORF, DE, vol. 56, no. 9, 1 Jan. 2006, pages 652-660) discloses the use of the combination of extracts of thyme herb and ivy leaves for the treatment of acute bronchitis; FAZIO S et al.: “Tolerance, safety and efficacy of Hedera helix extract in inflammatory bronchial diseases under clinical practice conditions: A prospective, open, multicenter postmarketing study in 9657 patients”, (PHYTOMEDICINE, GUSTAV FISCHER VERLAG, STUTTGART, DE, vol. 16, no. 1, 2009, pages 17-24) discloses a composition in the form of a syrup comprising dried Hedera helix extract; HOFFMANN D et al.: “Efficacy of dry extract of ivy leaves in children with bronchial asthma—a review of randomized controlled trials”, (PHYTOMEDICINE, GUSTAV FISCHER VERLAG, STUTTGART, DE, vol. 10, no. 2-3, 2003, pages 213-220) discloses a composition comprising dried ivy leaves for the treatment of chronic airway obstruction in children suffering from bronchial asthma. Although there are a large number of formulations comprising combination of herbal substance, the effects of a formulation comprising Hedera helix extract, Zingiber officinale extract and Pelargonium sidoides extract have been still unknown.
Products to be used for medical purposes have to incorporate the elements of quality, efficiency, and reliability. A product can be a “medical” product only by having these elements. In order for the product prepared from a herbal source to be used in medicine, it has to be prepared from an effective and a standardized extract, pharmacological, clinical outcomes and toxicological data thereof has to be established as well as stability of the product has to be determined. Therefore, it bears great significance to have a good stability for a product, produced from herbal sources, to be used in the treatment and prevention of diseases, or in the alleviation and/or elimination of the symptoms thereof.
Physical, chemical and microbiological factors play role in the stability of drugs or other products manufactured for medical purposes. The stability issue is not dependent on a simple cause only, but emerges as a result of many factors. Factors such as the interaction of active agents contained in a product, the interaction of excipients among themselves or with active agents, pH, light, humidity, and temperature are among many factors which may influence the stability of such products.
Until recently, researchers have deemed considerable importance on the chemical stability of the pharmaceutical products rather than the physical stability thereof and have conducted numerous studies on this subject. However, in many cases, they have demonstrated how the changes in the physical structure of the products are important for the quality of the product and for durability of technological, microbiological and biopharmaceutical properties thereof. Accordingly, it was shown that primarily the physical stability of a product has to be maintained in order to sustain its quality and other features thereof, and therefore ensuring the physical stability during the development of pharmaceutical products is as important as, or sometimes more important than ensuring the chemical stability thereof.
Additionally, the physical properties taken into account in the evaluation of the physical stability of a product, particularly the taste, scent, color, clarity, uniformity, etc. of a product, also considerably influence the patient compliance. For this reason, when a novel formulation is developed, besides aiming a formulation of good physical stability, the physical properties of this formulation should be made ideal to provide high patient compliance.
However, it is quite difficult to provide the above described conditions in the formulations comprising herbal substances. Due to some characteristic chemical, biological and physical properties of the herbal substances used in the formulation, some problems are encountered in obtaining a formulation comprising said substances as well as having a good physical stability and ideal physical properties in terms of patient compliance.
Physical properties and physical stability of the formulation are directly affected by the characteristic features of the herbal substances comprised therein. The herbal substance comprised in the formulation having physical properties such as a bad taste, bad scent, bad color, being easily oxidized and providing a suitable medium for reproduction of microorganisms, adversely affect the physical stability and physical properties of said formulation. Additionally, in case a formulation comprises a combination of herbal agents, a correct selection of the herbal agents bears great importance, since more than one herbal agent present in the same formulation are capable to mutually affect their respective properties.
Under the light of the foregoing, it would be desirable to provide a formulation, as well as a process for the preparation of this formulation, comprising combinations of herbal agents, being capable to retain the physical stability for a long time, and having ideal physical properties in terms of patient compliance.
In detail, there is a need in the state of art to a formulation comprising Hedera helix extract, Pelargonium sidoides extract and Zingiber officinale extract, and having ideal physical properties to ensure high patient compliance and good physical stability, as well as to a method for preparing this formulation, which is simple, cost-efficient and time-saving.